The rate of drug metabolism depends on various endogenous factors and pharmacokinetic-pharmacodynamic principles (Phase I[CYP450] or Phase II[conjugation], or both), plasma concentration, bioavailability, protein binding, solubility, rate of absorption among others.
Besides, age, underlying diseases, nutritional status, drug-drug interaction, and enzyme induction/inhibition, and genetic predisposition also affect the rate of drug metabolism. Some people are slow metabolizers while others are fast metabolizers.
Can anyone tell me which drugs are metabolized very slowly irrespective of the above given factors?
Hi
Differences in genetic (inherited) makeup among individuals affect what the body does to a drug and what the drug does to the body. The study of genetic differences in the response to drugs is called pharmacogenetics.
Because of their genetic makeup, some people process (metabolize) drugs slowly. As a result, a drug may accumulate in the body, causing toxicity. Other people metabolize drugs so quickly that after they take a usual dose, drug levels in the blood never become high enough for the drug to be effective.
In about half of the people in the United States, N -acetyltransferase, a liver enzyme that metabolizes certain drugs, works slowly. Such people are called slow acetylators. Drugs, such as isoniazid (which is used to treat tuberculosis), that are metabolized by this enzyme tend to reach higher blood levels and remain in the body longer in slow acetylators than they do in people in whom this enzyme metabolizes drugs rapidly (fast acetylators).
http://www.merckmanuals.com/home/drugs/factors-affecting-response-to-drugs/genetic-makeup-and-response-to-drugs
Genetic variation (polymorphisms-SNPS) accounts for some of the variability in the how different people respond to the same drug.
For example:
With N-acetyltransferases, individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly (split roughly 50 / 50 in the population of Canada). This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity.
http://cisncancer.org/research/what_we_know/advances/drug_metabolism.html
Drugs that undergoes lower uptake to the tissues where major metabolism occurs(liver) because of lower lipophilicity. will show slower metabolism. So, upto me lower lipophilic drugs will show slower metabolism because of lower uptake to the tissues. Hope you find it helpful.
The more hydrophilic sulindac tends to remain extracellular, whereas the more lipophilic sulfide accumulates inside the cell with cell/medium ratio of 50:1 (Duggan, 1981).
http://intl.pharmrev.org/content/49/4/403.full
I do not think there is an answer to your question. What determines the speed of drug metabolism is essentially the concentration of the enzyme and of course the kinetics of the drug to access the enzyme. Therefore one cannot cite a drug which is slowly metabolized independently of the factors you appropriately cite as determinants of its metabolic rate.
Thanks Dr.Brentano for your answer. But what about the drugs that have a very long half-life, and rather slowly eliminated from the body? Could these agents, say for instance, dutasteride, or fluoxetine, be good examples?
Regards, Sidharta
A very long half-life means slow disposition kinetics but half-life is the final result of complex mechanisms including "slow metabolism". I do not quite see what you mean by your question.
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